The ATP-binding cassette (ABC) transporters, also called the “traffic ATPases,” comprise a superfamily of over 100 membrane proteins that mediate transport and channel functions in prokaryotes and eukaryotes (See Higgins, C. F. (1992) Annu. Rev. Cell Biol. 8:67–113, and U.S. Pat. Nos. 5,858,719 and 6,030,806). ABC transporters share a similar overall structure and significant sequence homology. Typically ABC transporters have four conserved domains, two hydrophobic domains which may impart substrate specificity (Payne et al., Mol. Gen. Genet. 200:493–496, 1985; Foote et al., Nature 345:255–258, 1990; Anderson et al., Science 253:202–205, 1991; Shustik et al., Br. J. Haematol. 79:50–56, 1991; Covitz et al., EMBO J. 13:1752–1759, 1994), and two highly conserved domains associated with ATP binding and hydrolysis (Higgins, supra). ABC transporters govern unidirectional transport of molecules into or out of cells and across subcellular membranes (Higgins, supra). Their substrates range from heavy metals (Ouellette et al., Res. Microbiol. 142:737–746 1991) to peptides and full size proteins (Gartner et al., Nature Genet. 1:16–23 1992).
Eukaryotic ABC transporter proteins include: P-glycoproteins, also known as multidrug resistance (MDR) proteins, which are associated with resistance to a wide range of hydrophobic drugs (MDR1; Gottesman, M. M. & Pastan, I. (1993) Annu. Rev. Biochem. 62:385–427) or with phosphatidylcholine transport (MDR2; Ruetz, S. & Gros, P. (1994) Cell 77:1071–1081); CFTR, the cystic fibrosis transmembrane conductance regulator (Welsh, M. J. & Smith, A. E. (1993) Cell 73:1251–1254); TAP proteins, the transporters associated with antigen processing in mammalian cells (Androlewicz, M. J. et al. (1994) Proc. Natl. Acad. Sci. USA 91:12716–12720); cMOAT/cMRP1, which is associated with transport of glutathione, glucuronide, and sulfate conjugates across the canalicular membrane (Buchler, M. et al. (1996) J. Biol. Chem. 271:15091–15098); and STE6, which exports the a-factor mating pheromone of S. cerevisiae (Michaelis, S. (1993) Semin. Cell Biol. 4:17–27). Prokaryotic ABC proteins include periplasmic nutrient permeases, such as those responsible for uptake of maltose (MalFGK) and histidine (HisMPQ) in gram-negative bacteria, and toxin exporters such as those required for export of hemolysin (HlyB) and colicin (ColV) from E. coli (Higgins, supra). See U.S. Pat. No. 5,858,719.
Because of the important biological effects of ABC transporters, there is a need in the art to identify additional members of the ABC transporter family whose activity can be regulated to provide therapeutic effects.